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Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy.

Zhang CG, Zhu WJ, Liu Y, Yuan ZQ, Yang SD, Chen WL, Li JZ, Zhou XF, Liu C, Zhang XN - Sci Rep (2016)

Bottom Line: In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle).Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments.The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.

ABSTRACT
Co-delivery of chemotherapeutics and siRNA with different mechanisms in a single system is a promising strategy for effective cancer therapy with synergistic effects. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle). Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments. The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp. Moreover, almost all the Dox-siRNA-micelles accumulated in the tumor region beyond 24 h post-injection, and the co-delivery system significantly inhibited tumor growth with synergistic effects in vivo. This study demonstrated the effectiveness of Dox-siRNA-micelles in tumor-targeting and MDR reversal, and provided a promising strategy to develop a co-delivery system with synergistic effects for combined cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Intracellular drug accumulation of HepG2 or HepG2/ADM cells after treatment with Dox, Dox-micelle, and Dox–siRNA-micelle for different times.Drug uptake kinetic parameters obtained by non-linear fitting using Origin software (n = 3).
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f6: Intracellular drug accumulation of HepG2 or HepG2/ADM cells after treatment with Dox, Dox-micelle, and Dox–siRNA-micelle for different times.Drug uptake kinetic parameters obtained by non-linear fitting using Origin software (n = 3).

Mentions: The dynamic changes in intracellular Dox amount after treatment with different Dox formulations were measured and non-linearly fitted to simulate cellular uptake kinetics (Fig. 6). The uptake rate of Dox was faster than that of micelles, but no significant difference was observed between Dox-micelle and Dox–siRNAFAM-micelle both in HepG2 and HepG2/ADM cells. This finding might be due to the different uptake pathways of Dox and micelles. Dox entered cells via diffusion depending on the concentration difference between extracellular and intracellular environments, whereas micelle uptake occurred via endocytosis depending on the related protein on the cytomembrane. The extracellular Dox concentration was much higher than the intracellular Dox concentration, whereas the amount of related protein on the cytomembrane was limited. The elimination rate constant of Dox was also larger than that of Dox-micelle, indicating that the release process of Dox-micelle was slow, whereas Dox, as the substrate of P-gp, was effluxed immediately. The elimination rate constant of Dox–siRNA-micelle in HepG2/ADM cells was smallest, which suggested that siRNA was released from micelles in the cytoplasm, disturbed the translation of mdr1 mRNA, and downregulated the expression of P-gp, resulting in decreased efflux.


Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy.

Zhang CG, Zhu WJ, Liu Y, Yuan ZQ, Yang SD, Chen WL, Li JZ, Zhou XF, Liu C, Zhang XN - Sci Rep (2016)

Intracellular drug accumulation of HepG2 or HepG2/ADM cells after treatment with Dox, Dox-micelle, and Dox–siRNA-micelle for different times.Drug uptake kinetic parameters obtained by non-linear fitting using Origin software (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814909&req=5

f6: Intracellular drug accumulation of HepG2 or HepG2/ADM cells after treatment with Dox, Dox-micelle, and Dox–siRNA-micelle for different times.Drug uptake kinetic parameters obtained by non-linear fitting using Origin software (n = 3).
Mentions: The dynamic changes in intracellular Dox amount after treatment with different Dox formulations were measured and non-linearly fitted to simulate cellular uptake kinetics (Fig. 6). The uptake rate of Dox was faster than that of micelles, but no significant difference was observed between Dox-micelle and Dox–siRNAFAM-micelle both in HepG2 and HepG2/ADM cells. This finding might be due to the different uptake pathways of Dox and micelles. Dox entered cells via diffusion depending on the concentration difference between extracellular and intracellular environments, whereas micelle uptake occurred via endocytosis depending on the related protein on the cytomembrane. The extracellular Dox concentration was much higher than the intracellular Dox concentration, whereas the amount of related protein on the cytomembrane was limited. The elimination rate constant of Dox was also larger than that of Dox-micelle, indicating that the release process of Dox-micelle was slow, whereas Dox, as the substrate of P-gp, was effluxed immediately. The elimination rate constant of Dox–siRNA-micelle in HepG2/ADM cells was smallest, which suggested that siRNA was released from micelles in the cytoplasm, disturbed the translation of mdr1 mRNA, and downregulated the expression of P-gp, resulting in decreased efflux.

Bottom Line: In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle).Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments.The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.

ABSTRACT
Co-delivery of chemotherapeutics and siRNA with different mechanisms in a single system is a promising strategy for effective cancer therapy with synergistic effects. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle). Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments. The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp. Moreover, almost all the Dox-siRNA-micelles accumulated in the tumor region beyond 24 h post-injection, and the co-delivery system significantly inhibited tumor growth with synergistic effects in vivo. This study demonstrated the effectiveness of Dox-siRNA-micelles in tumor-targeting and MDR reversal, and provided a promising strategy to develop a co-delivery system with synergistic effects for combined cancer therapy.

No MeSH data available.


Related in: MedlinePlus